Androgens are a category of important gonadal steroid hormones in the human body. They promote the cell differentiation and t tissue growth by binding to the corresponding specific receptors, thereby participating in many crucial physiological functions, such as the formation of genital organs of male fetus (such as prostate, seminal vesicle, epididymis, etc.), the development and maintenance of secondary sex character and the generation of sperms. In both men and women, there are a certain proportion of androgens, such as androsterone, androstanediol and adrenosterone, etc. The androgens exert important physiological effects by binding to the androgen receptors (AR). The metabolic disorder and functional disorder of androgens or their receptors may induce various diseases or promote the disease courses, including prostatic hyperplasia, prostate cancer, male sterility, hirsutism, severe androgen-dependent alopecia and acne, etc. These diseases severely influence physical and mental health of patients, as well as greatly reduce their life quality.
Benign prostatic hyperplasia is a benign adenomatous hyperplasia of cells in the region around prostate urethra, but is not a cancer. It grows slowly and will not diffuse to other parts of the body. The benign prostatic hyperplasia is one of the most common diseases in urinary surgery, and has become an “invisible killer” threatening the health of men. The clinical statistics has indicated that, the incidence of benign prostatic hyperplasia is about 50% among men with 40-79 years of age, and may reach up to 80% after the age of 80. With a an increasing pressure of modern life style, the number of benign prostatic hyperplasia patients expand gradually and the onset age has a tendency to be younger. The benign prostatic hyperplasia disturbs the daily life of patients, and it is likely to cause many kinds of latent complications, such as acute urine retention, urinary tract infection, gross hematuria, bladder diverticulum, calculus, hydronephrosis and renal failure, etc. Clinical studies in the literature indicates that dihydrotestosterone in the patient body is the foremost inducement of benign prostatic hyperplasia.
Prostate cancer is a severe disease of elderly men, the morbidity and mortality thereof are very high in the West and occupies the first place of male malignant tumors [Landis S H, Murray T, 1998, CA Cancer J. Clin. 48, 6-29]. Although the incidence of prostate cancer in China is lower than in the West, with an increase in the aging population, changes of traditional dietary structure, and improvement of diagnosis of this disease, the incidence has elevated significantly in recent years. Clinical investigations have shown that the ages of patients tend to be younger, especially among people who require long-term sitting in work, such as computer operators and taxi drivers, etc. The etiology studies and clinical therapy practices of prostatic hyperplasia/prostate cancer have attracted extensive attention in the pharmaceutical industry world-wide.
AR protein is a member of the nuclear receptor superfamily, and functions as a ligand-activated transcription factor. As shown in FIG. 1, AR protein has three structural domains: N Terminal Domain (NTD), DNA Binding Domain (DBD) and Ligand Binding Domain (LBD) [He B, Kemppainen J A, 1999, J. Biol. Chem. 274(52), 37219-25]. Androgen forms a complex with LBD of AR, and binds to an Androgen Response Element (ARE) located in the promoter region of the AR target gene to exert the function of activating or inhibiting expression of target genes, thereby regulating the physiological functions of target tissue. Prostate is an important target organ for androgen. In the embryonic period, androgen binds to AR distributing in endoderm of urinary sinus to cause phenotype differentiation of prostate epidermal cells and to induce generation of prostate-specific proteins. In mature glandular organs, androgen promotes the mitosis and proliferation of prostate epithelial cells to maintain the morphology and function of the organ [Waller A S, Sharrard R M, 2000, J. Mol. Endocrinol. 24(3), 339-351]. In addition, the androgen also regulates prostate cell metabolic activities, such as biosynthesis of lipids, and control the generation of some prostate-specific expression proteins (for example, prostate-specific antigen, PSA), and the like.
The mechanism action of androgens and AR includes a set of complicated and precise signal transduction processes, and the specific binding of androgen to AR plays an indispensable role. Many AR related diseases results from the imbalance of the interaction between androgen and AR, due to the abnormal hormone levels or receptor dysfunction. In the individuals suffering from these diseases, medicines achieve the therapeutic effects through enhancing or inhibiting the activity of AR. Therefore, with AR as a target, finding chemicals with the activity to modulate AR's functions has become a focus of global efforts. According to pharmacological properties, AR modulators can be classified as AR agonist and AR antagonist. AR antagonist is an important means for treating prostatic hyperplasia/prostate cancer (especially for advanced stages), and it competitively binds to AR in the cancerous region, blocks the uptake of androgen by cells and inhibits the effect of androgen on target organs, thereby suppressing the growth of tumor cells, decreasing the tumor volume and postponing the disease course [Leewansangtong S, 1998, Endocrine-related Cancer 5, 325-339]. Comparing with other therapies of inhibiting androgen activities, such as orchidectomy, administration of luteinizing hormone releasing hormone analogs or testosterone synthetase (for example 5α-reductase) inhibitors, AR antagonist can block the binding of androgen to AR [Hong-Chiang, C, Hiroshi M, 1999, Proc. Natl. Acad. Sci. USA 96, 11173-11177] and overcome the shortcomings of anti-androgen therapies. In addition, AR antagonist can also be used to treat some common diseases, such as hirsutism, severe androgen-dependent alopecia (baldness) and acne, etc. At present, the widely used androgen antagonists can be divided into two categories: steroidal and non-steroidal. The steroidal drugs include cyproterone acetate (CPA) and the non-steroidal ones include flutamide, nilutamide and bicalutamide (Casodex), etc.
Non-steroidal AR antagonists have high selectivity to AR and do not cause hormone-like or anti-hormone effects on other steroid receptors, so they are accepted widely in the clinic. However, all the commercially available anti-androgens have many problems to be resolved. First, patients may suffer from various side-effects after administration, such as discomfort in the gastrointestinal tract, nausea, vomiting, insomnia, hypodynamia, headache, anxiety, blurred vision and hyposexuality, etc. Second, monotherapy with anti-androgen to treat prostatic hyperplasia/prostate cancer, patients will develop anti-androgen withdrawal syndrome (AWS). It shows a quick rise of the previously inhibited PSA levels and increased tumor volume after administration for a period of time. Treatment has to cease or other anti-androgen drugs must be used [Dicker A P, 2003, Lancet Oncol. 4(1), 30-36; Laufer M, Sinibaldi V J, 1999, Urology 54(4), 745]. The molecular mechanism of AWS is still unclear, but it is generally considered that, due to gene mutation of AR in prostate cells, the drugs which originally have AR antagonistic effects may produce agonist activity on AR. Therefore, there is an unmet medical demand for AR modulators with novel chemical structures.